Activation of early response genes by interferons (IFNs) and other cytokines requires tyrosine phosphorylation of a family of transcription factors termed signal transducer and activator of transcription (STAT) proteins. STAT proteins relay signals from activated cell surface receptors directly to the nucleus and have been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones.
The STAT protein is activated by the gp130 family of cytokines, e.g., the interleukin 6 (IL6) family of cytokines, epidermal growth factor, and leptin. Tyrosine-phosphorylated STAT3 binds to a specific DNA sequence in its target genes (Zhong et al. (1994); Akira et al. (1994)) and participates in signal transduction pathways activated by the IL6 family of cytokines and by epidermal growth factor (Zhong et al. (1995); Akira et al. (1994)). STAT3 is also activated in cells treated with leptin, a growth hormone that functions in regulating food intake and energy expenditure (Zhang et al. (1994)). Targeted disruption of the mouse gene encoding STAT3 leads to early embryonic lethality (Takeda et al. (1997)). Like other members of the STAT family, STAT3 becomes tyrosine phosphorylated by Janus kinases (JAKs). Phosphorylated STAT3 then forms a dimer and translocates into the nucleus to activate specific genes (Darnell et al. (1994)).
The invention relates to a family of protein inhibitors of activated STAT (PIAS) molecules that directly inhibit STAT function. This family includes but is not limited to, PIAS1, PIAS3, PIASxα, PIASxβ, and PIASy. Sequence analysis indicates that human PIAS1 is almost identical to a previously reported human protein named GBP (Gu/RH-II binding protein) (Shuai et al. Nature (1993)). However, GBP lacks 9 amino acid residues when compared with PIAS1. Further, GBP does not function as an inhibitor of STAT but was identified as a putative interaction protein of Gu/RNA helicase II.